Novel binuclear platinum complex and antitumor agent comprising this complex as active ingredient

ABSTRACT

Disclosed are a binuclear platinum complex including di-μ-sulfoacetato-bis[1,2-diaminocyclohexane-platinum (II)] and isomers thereof, and an antitumor agent comprising this complex as an effective ingredient. 
     This complex has a high antitumor activity and lower adverse side effects such as nephrotoxicity.

TECHNICAL FIELD

The present invention relates to a novel platinum complex having anantitumor activity, which is valuable as a medicine such as an antitumoragent, and to an antitumor agent comprising this complex as an activeingredient.

BACKGROUND ART

Some platinum complexes represented by cisplatin [namely,cis-diamminedichloro platinum (II)] show a prominent antitumor effect,and are applied as chemotherapeutic agents for malignant tumors tovarious disease cases.

Cisplatin, however, has a very strong toxicity such as nephrotoxicity,and therefore, the remedial affect of cisplatin is hindered by thisstrong toxicity.

Second generation platinum complexes represented by platinum (II)cis-diammine-1,1-cyclobutanedicarboxylate, carboplatin, were developed,and although the nephrotoxicity is moderated in these platinumcomplexes, the antitumor activity is lower than that of cisplatin.

Accordingly, the development of a chemotherapeutic agent having atoxicity lower than those of the conventional platinum complexes, and ahigher antitumor effect, is desired.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a molecular depiction of one composition within the scope ofthe invention; e.g. see Example 1.

DISCLOSURE OF THE INVENTION

The inventors carried out investigations with a view to solving theabove-mentioned problem, and have proposed a novel seleniousacid-platinum complex and an antitumor agent comprising this complex asan active ingredient (Japanese Patent Application No. 63-176828). Afterfurther investigations, the inventors found a novel binuclear platinumcomplex having a high antitumor effect, and as a result, completed thepresent invention.

More specifically, in accordance with the present invention, there areprovided a novel binuclear platinum complex represented by the followingformula I, II or III,di-μ-sulfoacetate-bis[(cis-diaminocyclohexane)platinum (II)] and anantitumor agent comprising the platinum complex as an active ingredient:##STR1##

BEST MODE OF CARRYING OUT THE INVENTION

The novel binuclear platinum complex of the present invention(hereinafter referred to as the compound of the present invention) canbe obtained, for example, in the following manner.

Namely, a dinitrato-platinum complex containing 1,2-diaminocyclohexaneas the carrier ligand is used as the starting material, and the platinumcomplex is brought into contact with an OH⁻ type anion exchange resin,to convert the nitrato group to a hydroxyl group, and then reacted withsulfoacetic acid.

As specific examples of the dinitrato-platinum complex, there can bementioned dinitrato(1,2-diaminocyclohexane)platinum (II),dinitrato(1,2-diaminoethane)platinum (II), and dinitratodiammineplatinum(II).

As the OH⁻ anion exchange resin, there can be mentioned Diaion SA10AOH(supplied by Mitsubishi Kasei).

When the platinum complex is brought into contact with the anionexchange resin, any batch method and column method can be adopted, solong as a good contact between the resin and the platinum complex isobtained. From the viewpoint of efficiency, the column method ispreferable.

For reacting the obtained reaction mixture with sulfoacetic acid,preferably sulfoacetic acid is incorporated and dissolved in thereaction mixture and the resulting mixture allowed to stand for about 30minutes to about 2 hours. After the reaction, the solution isconcentrated to precipitate a crystal, and the crystal is recovered byfiltration and dried to obtain the intended compound.

In the case of the dinitrato-platinum complex valuable as the startingmaterial of the compound of the present invention, for example,dinitrato(diaminocyclohexane)platinum (II), there are consideredtrans-compounds represented bydinitrato-(1R,2R)-diaminocyclohexaneplatinum (II) anddinitrato-(1S,2S)-diaminocyclohexaneplatinum (II), and cis-compoundsrepresented by dinitrato-cis-diaminocyclohexaneplatinum (II). For thecis-compound, at least three structures including a conformer areconsidered.

Accordingly, the compound of the present invention includes all ofisomers synthesized according to the starting material.

The antitumor effect of the compound of the present invention will nowbe described with reference to the following test example.

TEST EXAMPLE (antitumor effect test to mouse leukemia L1210 cells)

1×10⁵ of mouse leukemia L1210 cells were transplanted in the abdominalcavity of a 2-weeks-old male CDF₁ mouse, and the compound obtained inany of the examples given hereinafter was administered to the abdominalcavity three times at intervals of 4 days from the day succeeding thetransplantation. Similarly, only a physiological saline solution wassimilarly administered in the control group.

The effect of the antitumor action was evaluated by calculating the lifeprolongation ratio (T/C value) from the average number of survival daysin the compound-administered group and the control group according tothe following formula: ##EQU1##

The T/C values obtained in the compound-administered groups are shown inTable 1.

                  TABLE 1                                                         ______________________________________                                                       Amount                                                                        Administered                                                                  (mg/kg)  T/C (%)                                               ______________________________________                                        Compound obtained                                                                              25         128                                               in Example 1     12.5       269                                                                6.25       230                                               Compound obtained                                                                              25         301                                               in Example 2     12.5       141                                               Compound obtained                                                                              25         335                                               in Example 3     12.5       383                                               ______________________________________                                    

From the foregoing results, it was confirmed that the compound of thepresent invention has an excellent anti-tumor activity. During thepresent test, no side effects such as the nephrotoxicity were observedat all.

When the acute toxicity test of the compound of the present inventionwas carried out by using a mouse of the ICR line, it was found that, inthe case of the administration into the abdominal cavity, the LD₅₀ ofthe compound obtained in Example 1 was 30.4 mg/kg.

Accordingly, it is understood that the compound of the present inventionhas an excellent antitumor activity and is valuable as a very safeantitumor agent.

The dose and preparation form of the compound of the present inventionwill now be described.

The compound of the present invention can be administered to animals andmen directly or together with a usual pharmaceutical carrier. Theadministration form is not particularly critical, and an appropriateadministration form can be selected according to need. Tablets,capsules, granules, fine granules and powders can be used for oraladministrations, and injections and suppositories can be used fornon-oral administrations.

The appropriate doses differ according to the age and body weight of apatient, and the degree of a disease, but to obtain an intended effectby an oral administration, it is considered preferable to dividedlyadminister the compound of the present invention in a dosage of 10 to600 mg for an adult, several times per day.

Medicines for the oral administration are prepared by using, forexample, starch, lactose, refined sugar, mannitol, carboxymethylcellulose, corn starch, an inorganic salt and the like, by customaryprocedures.

In addition to the foregoing excipients, a binder, a disintegratingagent, a surface active agent, a flowability improver, a taste improver,a colorant, a perfume and the like can be used for the formation ofmedicines, according to need. Specific examples of these agents aredescribed below.

Binders

Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylcellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, and macrogol.

Disintegrating Agents

Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, carboxymethyl cellulose, and lowly substitutedhydroxypropyl cellulose.

Surface Active Agents

Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, andpolysorbate 80.

Lubricants

Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester,magnesium stearate, calcium stearate, aluminum stearate, andpolyethylene glycol.

Flowability Improvers

Light silica, dry aluminum hydroxide gel, synthetic aluminum silicate,and magnesium silicate.

The compound of the present invention also can be administered in theform of a suspension, an emulsion, a syrup or an elixir. A preparationform of this type can contain a taste or smell improver and a colorant.

To obtain the intended object by a non-oral administration, it isconsidered preferable to administer 5 to 200 mg of the compound of thepresent invention per day for an adult by intravenous injection,intravenous drip, hypodermic injection or intramuscular injection.

Non-oral medicines are prepared by customary procedures and as thediluent, there are generally used distilled water for injection,physiological saline solution, an aqueous solution of glucose, avegetable oil for injection, sesame oil, coconut oil, soybean oil, cornoil, propylene glycol, and polyethylene glycol. Furthermore, afungicide, an antiseptic agent, and a stabilizer can be added accordingto need. In view of the stability, a method can be adopted in which anon-oral medicine is filled in a vial or the like and frozen, water isremoved by a usual freeze-drying technique, a solution is formed fromthe freeze-dried product again just before administration, and thesolution is then administered. Moreover, an isotonic agent, astabilizer, an antiseptic agent, and an analgetic agent can be addedaccording to need.

As another non-oral medicine, there can be mentioned coating agents suchas an external lotion and a cream, and suppositories for rectaladministration, and these non-oral medicines are prepared by customaryprocedures.

The present invention will now be described in detail with reference tothe following examples, that by no means limit the scope of theinvention.

EXAMPLE 1

In 100 ml of distilled water was dissolved under heating 4.30 g ofdinitrato-(1R,2R)-diaminocyclohexaneplatinum (II) having1,2-diaminocyclohexane as the carrier ligand, the solution was passedthrough a column packed with 160 ml of Diaion SA10AOH, and an elutionwas effected with distilled water. Then 1.40 g of sulfoacetic acid(supplied by Aldrich) was dissolved as a dissociating acid into theeluate, and the solution was heated at 60° C. for 1 hour andconcentrated by a rotary evaporator. When the volume was reduced to 30ml, the evaporation was stopped, the precipitated crystal was recoveredby filtration, and the obtained solid was thoroughly washed withdistilled water and air-dried to obtain a light yellow solid.

From the following physical and chemical properties thereof, this lightyellow solid was identified asdi-μ-sulfoacetato-bis[(1R,2R)-diaminocyclohexaneplatinum (II)]trihydrate.

Yield:

3.2 g (72%)

Elementary analysis:

Calculated value: C=20.25%, H=4.04%, N=5.91%, S=6.76%

Found value: C=20.25%, H=3.93%, N=5.99%, S=6.76%

Single crystal X-ray structural analysis:

orthrhombic, molecular weight Fw=948.80

Space group:

P2₁ 2₁ 2₁

Unit lattice:

a=19.186 (4) Å

b=14.577 (2) Å

c=9.876 (1) Å

(four molecules are contained per unit lattice)

Calculated density:

D_(x) =2.28 g/cm³

Measured density:

D_(m) =2.25 g/cm³

R value:

0.033 (wR=0.031)

V value:

V=2762 (1) Å³

Note, 2455 independent reflections were used for the structuralanalysis.

The molecular diagram of this compound based on the single crystal X-raystructural analysis is shown in FIG. 1.

EXAMPLE 2

A light yellow solid was prepared in the same manner as described inExample 1, except that 4.30 g ofdinitrato-(1S,2S)-diaminocyclohexaneplatinum (II) having1,2-diaminocyclohexane as the carrier ligand was used.

From the following physical and chemical properties thereof, this lightyellow solid was identified asdi-μ-sulfoacetato-bis[(1S,2S)-diaminocyclohexaneplatinum (II)]trihydrate.

Yield:

3.2 g (72%)

Elementary analysis:

Calculated values: C=20.25%, H=4.04%, N=5.91%, S=6.76%

Found values: C=20.04%, H=4.02%, N=5.97%, S=6.57%

EXAMPLE 3

A light yellow solid was prepared in the same manner as described inExample 1, except that 4.30 g ofdinitrato-cis-diaminocyclohexaneplatinum (II) havingcis-diaminocyclohexane as the carrier ligand was used.

From the following physical and chemical properties thereof, this lightyellow solid was identified asdi-μ-sulfoacetato-bis[cis-diaminocyclohexaneplatinum (II)] trihydrate.

Yield:

3.2 g (72%)

Elementary analysis:

Calculated value: C=20.25%, N=4.04%, N=5.91%, S=6.76%

Found values: C=20.42%, H=3.94%, N=5.84%, S=6.76%

EXAMPLE 4

    ______________________________________                                        (1)    Corn starch            52     g                                        (2)    Crystalline cellulose  40     g                                        (3)    Calcium carboxymethyl cellulose                                                                      5      g                                        (4)    Light silica           0.5    g                                        (5)    Magnesium stearate     0.5    g                                        (6)    Compound obtained in Example 1                                                                       2      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1) through (6) werehomogeneously mixed, and the mixture was compression-molded by atableting machine to obtain tablets each having a weight of 200 mg.

Each tablet contained 4 mg of the compound obtained in Example 1, and 3to 50 tablets were dividedly administered to an adult, several times perday.

EXAMPLE 5

    ______________________________________                                        (1)    Crystalline cellulose  92.5   g                                        (2)    Magnesium stearate     0.5    g                                        (3)    Calcium carboxymethyl cellulose                                                                      5      g                                        (4)    Compound obtained in Example 2                                                                       2      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1) and (4) and apart of component (2) were homogeneously mixed, and the mixture wascompression-molded and pulverized. Then component (3) and the remainderof component (2) were added to the pulverization product, and themixture was compression-molded by a tableting machine to obtain tabletseach having a weight of 200 mg.

Each table contained 4 mg of the compound obtained in Example 2, and 3to 50 tablets were dividedly administered to an adult, several times perday.

EXAMPLE 6

    ______________________________________                                        (1)    Crystalline cellulose  42.5   g                                        (2)    10% solution of hydroxypropyl                                                                        50     g                                               cellulose in ethanol                                                   (3)    Calcium carboxymethyl cellulose                                                                      5      g                                        (4)    Magnesium stearate     0.5    g                                        (5)    Compound obtained in Example 3                                                                       2      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1), (2) and (5)were homogeneously mixed, and by customary procedures, the mixture waskneaded, granulated by an extrusion granulator, dried, anddisintegrated. Then the disintegration product was mixed with components(3) and (4) and the mixture was compression-molded by a tabletingmachine to obtain tablets each having a weight of 200 mg.

Each tablet contained 4 mg of the compound obtained in Example 3, and 3to 50 tablets were dividedly administered to an adult, several times perday.

EXAMPLE 7

    ______________________________________                                        (1)    Corn starch            93     g                                        (2)    Magnesium stearate     0.5    g                                        (3)    Calcium carboxymethyl cellulose                                                                      5      g                                        (4)    Light silica           0.5    g                                        (5)    Compound obtained in Example 1                                                                       1      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1) through (5) werehomogeneously mixed, compression-molded by a compression moldingmachine, pulverized by a pulverizer, and classified to obtain a granule.

This granule contained 10 mg of the compound obtained in Example 1 pergram of the granule, and 1 to 20 g of the granule was dividedlyadministered to an adult, several times per day.

EXAMPLE 8

    ______________________________________                                        (1)    Crystalline cellulose  69     g                                        (2)    10% solution of hydroxypropyl                                                                        30     g                                               cellulose in ethanol                                                   (3)    Compound obtained in Example 2                                                                       1      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1) through (3) werehomogeneously mixed, and the mixture was kneaded, granulated by anextrusion granulator, dried, and classified to obtain a granule.

The granule contained 10 mg of the compound obtained in Example 2 pergram of the granule, and 1 to 20 g of the granule was dividedlyadministered to an adult, several times per day.

EXAMPLE 9

    ______________________________________                                        (1)    Corn starch            97.5   g                                        (2)    Light silica           0.5    g                                        (3)    Compound obtained in Example 3                                                                       2      g                                               Total                  100    g                                        ______________________________________                                    

According to the above-mentioned recipe, components (1) through (3) werehomogeneously mixed, and the mixture was filled in capsules No. 2 sothat each capsule contained 200 mg of the mixture.

Each capsule contained 4 mg of the compound obtained in Example 3, and 3to 50 capsules were dividedly administered to an adult, several timesper day.

EXAMPLE 10

    ______________________________________                                        (1)   Distilled water for injection                                                                       Appropriate                                                                   amount                                            (2)   Glucose                 200    mg                                       (3)   Compound obtained in Example 1                                                                        100    mg                                             Total                   5      ml                                       ______________________________________                                    

Components (2) and (3) were dissolved in distilled water for injection,and the solution was poured in an ampoule having a capacity of 5 ml andsterilized under pressure at 121° C. for 15 minutes to obtain aninjection.

We claim:
 1. A binuclear platinum complex represented by the followingformula I: ##STR2##
 2. A binuclear platinum complex represented by thefollowing formula II. ##STR3##
 3. A binuclear platinum complexrepresented by the following formula III: ##STR4## 4.Di-μ-sulfoacetato-bis[(cis-diaminocyclohexane)platinum (II)].
 5. Anantitumor agent comprising as an effective ingredient a binuclearplatinum complex represented by the following formula: ##STR5##
 6. Anantitumor agent comprising as an effective ingredient a binuclearplatinum complex represented by the following formula: ##STR6##
 7. Anantitumor agent comprising as an effective ingredient a binuclearplatinum complex represented by the following formula: ##STR7##
 8. Anantitumor agent comprisingdi-μ-sulfoacetato-bis-[(cis-diaminocyclohexane)platinum (II)] as aneffective ingredient.